Rapamycin characterized by Findlay and co-workers in 1978 is a 35-membered macrolide isolated from S. hygroscopicus (Can. J. Chem., 1978, 56, 2491, J. Antibiotics, 1975, 28, 721, U.S. Pat. No. 3,929,992, issued Dec. 30, 1975, U.S. Pat. No. 3,993,749, issued Nov. 23, 1975. Rapamycin has been found to have antifungal activity, particularly against Candida albicans, both in vitro and in vivo (J. Antibiotics, 1978, 31, 539).
Rapamycin alone (U.S. Pat. No. 4,885,171) or in combination with picibanil (U.S. Pat. No. 4,401,653) has been shown to have antitumor activity. R. Martel et al. (Can. J. Physiol. Pharmacol, 55, 48 (1977) disclosed that rapamycin is effective in an experimental allergic encephalomyelitis model, a model for multiple sclerosis; in an adjuvant arthritis model, a model for rheumatoid arthritis; and effectively inhibited the formation of IgE-like antibodies.
The immunosuppressive effects of rapamycin have been disclosed (FASEB 3, 3411 (1989); Med. Sci. Res., 1989, 17, 877). Cyclosporin A and FK-506, other macrocyclic molecules, also have been shown to be effective as immunosuppressive agents, therefore useful in preventing transplant rejection (FASEB 3, 3411 (1989); FASEB 3, 5256 (1989); and Lancet 1183 (1978)).
Fujisawa United States patents (U.S. Pat. No. 4,929,611, issued May 29, 1990 and U.S. Pat. No. 4,956,352, issued Sep. 11, 1990) disclose the use of FK-506-type compounds in treating resistance to transplantation. A Sandoz European patent application (EPO Publication No. 0,315,978) discloses the use of FR-900506 and related compounds in the topical treatment of inflammatory and hyperproliferative skin diseases and of cutaneous manifestations of immunologically-mediated illness. A Fisons World patent application (PCT Publication WO 90/14826) discloses the use of FR-900506 and related compounds in the treatment of reversible obstructive airways disease, particularly asthma. A Fujisawa European patent application (EPO Publication No. 0,423,714) discloses the use of FK-506 and derivatives as hair revitalizing agents. Various studies have suggested the efficacy of FK-506 in the treatment of a number of ailments, including rheumatoid arthitis (C. Arita, et al., Clincial exp. Immunol., 1990, 82, 456-461; N. Inamura, et al., Clin. Immunol. Immunopathol. 1988, 46, 82-90), recent-onset diabetes (N. Murase, et al., Diabetes, 1990, 39, 1584-86; N. Murase, et al., Lancet, 1990, 336, 373-74), posterior uveitis (H. Kawashima, Invest. Ophthalmul. Vis. Sci., 1988, 29, 1265-71), hepatic injury associated with ischemia (M. Sakr, et al., Life Sci., 1990, 47, 687-91) allergic encephalomyelitis (K, Deguchi, et al., Brain Nerve, 1990, 42, 391-97), glomerulonephritis (J. McCauley, et al., Lancet, 1990, 335, 674), systemic lupus erythematosus (K. Takabayashi, et al., Clin. Immunol. Immunopathol., 1989, 51, 110-117), multidrug resistance (M. Naito, et al., Cancer Chemoether. Pharmacol., 1992, 29, 195-200), inflammation of mucosa and blood vessels (PCT Publication WO 91/17754), cytomegalovirus infection (UK Publication GB 2,247,620A), and idiopathic thrombocytophenic purpura and Basedow's disease (PCT Publication WO 91/19495).
Mono- and diacylated derivatives of rapamycin (esterified at the 31 and 42 positions) have been shown to be useful as antifungal agents (U.S. Pat. No. 4,316,885) and have been used as water soluble prodrugs of rapamycin (U.S. Pat. No. 4,650,803 and PCT Patent Publication WO 92/21341). Reduction products of rapamycin have been prepared (U.S. Pat. Nos. 5,102,876 and 5,138,051). Derivatives of rapamycin at the 31 and 42 positions which have been disclosed include: carboxylic acid esters (PCT Patent Publication WO92/05179); carbamates (U.S. Pat. No. 5,118,678); amide esters (U.S. Pat. No. 5,118,677); fluorinated esters (U.S. Pat. No. 5,100,883); acetals (U.S. Pat. No. 5,151,413); and silyl ethers (U.S. Pat. No. 5,120,842). In addition, bicyclic derivatives of rapamycin connected via the 31, 42 positions (U.S. Pat. No. 5,120,725) and rapamycin dimers connected via the 42 position (U.S. Pat. No. 5,120,727) have been disclosed. Various aryl(lower alkyl) and heteroaryl derivatives of FK-506 type compounds have also been disclosed (UK Patent Publication No. GB 2,245,891A). O-Aryl, O-alkyl, O-alkenyl and O-alkynyl derivatives of FK-506 type compounds have been disclosed (EPO Patent Publication No. 0,515,071).